Chlorophenyl-butadienols

ABSTRACT

1-Chlorophenyl-2,3-butadien-1-ols, e.g., 2-(o-chlorophenyl)-3,4pentadien-2-ol, and their preparation are described. The compounds are useful as anti-inflammatories.

Unlted States Patent 3,929,906

Anderson Dec. 30, 1975 [54] CHLOROPHENYL'BUTADIENOLS FOREIGN PATENTS OR APPLICATIONS [75] Invent Paul Anderson, Dover, 2,258,349 6 1973 Germany 260 618 R [73] Assignee: Sandoz, 1110., E. Hanover, NJ. OTHER PUBLICATIONS 1 Filed? 1973 Petrov et al., Chem. Abstracts, Vol. 54, 8677b; 21 App]. No.: 429,664

Primary Examiner-Donald G. Daus 52 US. Cl 260 618 D; 260/2475; 260/247.7; Assistant Springer 260/34gg ggiig g zigg g Attorney, Agent, or Firm-Gerald D. Sharkin; Richard E. Vila; Frederick H. Weinfeldt R; 260/570.6; 260/618 D; 260/618 R; 260/567.6; 424/330; 424/340, 424/343 [51] Int. Cl. C07C 35/21 [57] ABSTRACT 58] Field 61 Search 260/618 D '1-Chl9r9Pheny1-2,3-butadlen-l-ols, -8; chlorophenyl)-3,4-pentadien-2-ol, and then prepara- 5 References Cited tion are described. The compounds are useful as anti- UNITED STATES PATENTS nflammawles- 2,591,611 5/1952 ROSS 260/618 D 5 Claims, N0 Drawings CHLOROPHENYL-BUTADIENOLS This invention relates to substituted 2,3-butadienols, and more particularly, to l-chlorophenyl-2,3-butadienl-ols, as well as to pharmaceutical compositions containing such compounds and to the pharmaceutical use of such compounds.

The compounds of this invention may be conveniently represented by theformula l:

wherein R is a hydrogen atom, methyl or ethyl, preferably methyl; and A is either o-chlorophenyl or m-chlorophenyl, i.e.,

Compounds I are obtainable by reducing with a complex metal hydride, a corresponding alkynol cornpound of the formula ll, (process a):

wherein A and R are as defined above; and L is either a. a quaternary ammonium radical;

b. an ether selected from the group consisting of tetrahydrofuran-Z-yloxy; tetrahydropyran-Z- yloxy or 4-methoxy-tetrahydropyran-4-yloxy;

c. halo having an atomic weight of from about 19 to I27, e.g., fluoro, chloro, bromo or iodo; or

d. a sulfonyloxy radical.

The complex hydride reducing agents may be of the formula Illa or lllb: I

2 hpZ-i -H llla, or i-H lllb borohydride, lithium gallium hydride, magnesium aluminum hydride,-lithium diisobutylmethyl aluminum hydride, lithium trimethoxy aluminum hydride, diethyl aluminum hydride and diborane, preferably lithium aluminum hydride or sodium dihydrobis (2-methoxye- .thoxy) aluminate.

The complex hydrides (Illa and lllb) are either known and-may be prepared by methods described in the literature or where not known may be prepared by methods analogous to those for preparing the known compounds. Many of the complex hydrides are commercially available.

Process a) should be carried out in a medium which is not detrimental to the reaction, such as in an aprotic organic solvent, e.g., an ether such as diethyl ether, tetrahydrofuran or dioxane, an aromatic medium, such as benzene, toluene or pyridine or a saturated aliphatic hydrocarbon, such as pentane, hexane or octane. The

,medium may be a mixture or a single material. The

reaction may, for example, be carried out at about -40 to +l20C., e.g., at the boiling point of the medium. However, temperatures of from about l0 to +50C. are preferred. While the higher temperatures resultin a faster reaction rate, reactions carried out at lower temperatures tend to give purer products. The reaction product (21 Compound I) may be recovered by conventional means, e.g., by carefully adding a small amount of water or aqueous solution, e.g., aqueous ammonium chloride, or sodium hydroxide to the reaction mixture, filtering off the inorganic by-products or hydrolysis productsof the hydride ion source, and then separating the Compound 1 product from the organic phase by such means as precipitation, extraction, crystallization, chromatography or liquid-liquid extraction. As will be appreciated by those skilled in the art, it is preferred to exclude moisture from the reaction, e.g., by use of anhydrous solvents and conditions. The reaction may be advantageously carried out in an inert atmosphere, e.g., under nitrogen gas.

The compounds of formula II in which L is a quaternary ammonium radical are compounds of formula lla:

wherein A and R are as defined above; and L is the radical:

wherein R and R independently represent-alkyl having 1 to 4 carbon atoms; unsubstituted cycloalkyl having 5 to 6 ring carbons, i.e., cyclopentyl or cyclohexyl; or together, with N, represent a heterocyclic ring having 5 to 7 members selected from the group consistingof unsubstituted pyrrolidino, piperidino, homopiperidino, morpholino, and their alkyl subst-ituted derivatives containing from I to 3 alkyl groups of l to 4 carbon atoms;

R represents alkyl having 1 to4 carbon atoms, e.g., methyl, ethyl, propyl or butyl including isomeric forms where they exist, although the unbranched alkyls are preferred, especially methyl, and

X is an anion derived from a mineral acid or an organic sulfonic acid, provided that X is not fluoro, e.g., iodo or methylsulfonyl. I

Compounds Ila can be prepared by quaternizing a compound of the formula V:

wherein R and X are as defined above. The quaternization can be carried out in the conventional manner, e.g., in a suitable solvent such as acetone, at a temperature of from to +30C., neither the solvent nor the temperature being critical. A preferred-compound Vl is methyl iodide. The compounds of formula VI are known per se or can beprepared from known materials by conventional methods,'and many are commercially available.

The compounds of formula ll in which L is an ether moiety, i.e., the compounds of formula llb:

A- cEc cH, -L" llb wherein A and R are as defined above, and L" is tetrahydrofuran-Z-yloxy, tetrahydrOpyran-Z- yloxy or 4-methoxy-tetrahydropyran-4-yloxy can be prepared by reacting a compound of the formula Vll A I=O Vll wherein A and R are defined above, with Grignard reagent formed by treating a compound of the formula Vlll:

HcEc-cm-L" vm wherein L" is as defined above, with ethyl, magnesium bromide in the conventional manner for carrying out Grignard reactions.

The compounds of formulae Vll and VIII used in the production of compounds llb are known or can be prepared from known compounds-usingv conventional techniques.

The compounds of formula II in which L is halo other than iodo, i.e., these compounds of formula llc:

wherein r A and R are as defined above, and

L' is fluoro, chloro or bromocan be prepared by reacting a compound of the formula IX: 4

wherein A and R are as defined above with the appropriate'halide selected from the group of thionyl chloride or bromide, phosphorus pentachloride or bromide and hydrocarbon sulfonyl fluorides, e.g.,

benzyl sulfonyl fluoride, tosyl fluoride and mesyl fluoride, in an organic medium such as hexane, benzene or dimethoxyglycol. Forthe chlorination and bromination a tertiary amine base, such as pyridine, is included in the reaction mixture and the reaction temperature is about 0 .to 20C. For the fluorination the reaction temperature is 0 to about 150C.

Compounds of formula ll in which L is iodo are conveniently prepared by reacting corresponding compounds of formula He in which L' is chloro, with sodium iodide in acetone, the reaction being carried out in conventional manner for replacing a chloro with an iodo.

The compounds of formula II in which L is a sulfonyloxy radical are compounds of formula lId:

wherein A and R are as defined above, and

L 'is a sulfonyloxy radical which may be either alkylsulfonyloxy in which the alkyl group may be substituted, e.g., halo, or unsubstituted and contain from 1 to as many as 16 or more, preferably 1 to 6 carbon atoms, e.g., methane sulfonyloxy, ethanesulfonyloxy, 3chloropropanesulfonyloxy, or l-hexadecanesulfonyloxy; or arylsulfonyloxy in which the aryl group is phenyl, naphthyl or substituted phenyl, which may have from 1 to 3 substituents independently selected from the group consisting of alkyl of l to 6 carbon atoms, alkoxy of l to 6 carbon atoms, halo and nitror' Compounds lId can beprepa'red by reacting a compound of the formula lX above with an appropriate chloride or- Z-naphthalenesulfonyl chloride. This reacroorh temperature: r

The compounds of formula l-X used in the production of compounds lIc and lld-c'an be prepared by convention is conveniently carried out in "pyridine ator about tional hydrolysis of a compound of formula IIb, such as with a mineral or organic acid.

The compounds of formula V used in the preparation of Compounds IIa, above, can be prepared by reacting a compound of formula VII above with a compound of formula XI:

wherein R and R are as defined above. This reaction may be carried out at temperatures of 0 to 50C., conveniently at room temperature, and in the presence of an organic solvent such as tetrahydrofuran.

The compounds of formula XI are known or can be produced in known manner by reacting a compound of the formula XIV:

wherein R and R are as defined above, with lithium metal at a temperature of 0 to 50C. in a suitable solvent such as ethylene diamine.

The compounds of formula V can also be prepared by a process (b) which involves reacting a compound of formula XII:

wherein A and R are as-defined above, with a compound of formula XIII:

wherein R and R are as defined above.

In process b), a compound of formula XII is reacted with a compound of formula XIII at a temperature of to 50C. preferably at room temperature, in the presence of an inert solvent, and in the presence of mono-valent coinage metal ion, e.g., copper ion, as

catalyst, preferably cuprous chloride or cuprous oxide, although salts and the like of other coinage metals, i.e., silver and gold (I), can likewise be used. The compounds of formula XII can be prepared by reacting a compound of formula VII above in a solvent such as dimethylacetamide or dimethylsulfoxide with a suitable acetylene reagent, such as sodium or lithium acetylide conveniently at room temperature.

The compounds of formulae XIII and XIV used in the above-identified preparations of compounds V are known or can be produced from known materials by conventional techniques, and many are commercially available.

The compounds of formula (I) are useful because they possess pharmacological activity in animals. In particular, the compounds (I) are useful as anti-inflammatory agents as indicated by the Carrageenan induced edema test on rats (oral administration at I to 200 mg/kg). For such use, the compounds may be combined with a pharmaceutically acceptable carrier, and such other conventional adjuvants as may be necessary, and administered orally in such forms as tablets and capsules, elixirs, suspensions and the like or parenterally in the form of an injectable solution or suspension. The dosage administered will, of course, vary depending upon the compounds used and the mode of administration. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 1 milligram to about 250 milligrams per kilogram, e.g., from about 1 milligram to about 175 milligrams per kilogram of body weight, preferably given in divided doses 2 to 4 times a day, or in sustained release form. For most mammals, the administration of from about milligrams to about 3000 milligrams, e.g., from about I60 milligrams to about 2000 milligrams, of the compound per day provides satisfactory results and dosage forms suitable for internal administration comprise fromabout 25 milligrams to about 1500 milligrams, e.g., from about 40 milligrams to about 1000 milligrams, of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

For the above usage, oral administration with carriers may take place in such conventional forms as tablets, dispersible powders, granules, capsules, syrups and elixirs. Such compositions may be prepared according to any method known in the art for manufacture or pharmaceutical compositions, and such compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving-agents, in'order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preseratives (ethyl-phydroxybenzoate). Capsules preferably contain the active ingredient admixed with an inert diluent, e.g., calcium carbonate, calcium phosphate, kaolin, polyethylene glycol, peanut oil or sesame oil. The preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly tablets or solid or liquid diluentfilled capsules, as appropriate to the nature of the particular active ingredient.

Representative formulations for administration, 2 to 4 times a day, in treating inflammation are liquid-filled, soft gelatin capsules prepared by conventional techniques and containing the following:

7 In the following example which is illustrative of the invention, temperatures are in degrees Centigrade, and room temperature is 20 to 30C., unless indicated otherwise.

EXAMPLE 2-(o-chlorophenyl)-3,4-pentadien-2-ol.

Step A To a Grignard mixture prepared form 17.5 g bromoethane and 3.84 g of magnesium in a total of 125 ml. of dry tetrahydrofuran, 20.2 g of 3-(2'-tetrahydropyranyloxy) propyne is added dropwise. After standing for a few minutes at room temperature, the mixture is heated for 40 minutes at 50C. The mixture is cooled to room temperature, then 25 g of 2'- chloroacetophenone is added dropwise. Upon completion of the addition, the mixture is heated at reflux for minutes. The mixture is cooled, poured onto ice and extracted with chloroform thrice. The combined chloroform extracts are dried over anhydrous magnesium sulfate, filter and then evaporated to dryness to yield crude 2-(o-chlorophenyl)-5-(2'-tetrahydropyranyloxy)-3-pentyn-2-ol.

Step B 45.2 g of the crude product from Step A is dissolved in 300 ml. of dry tetrahydrofuran. The solution is cooled in an ice bath to 5C., then 85 ml. of a 70% (w/v) solution of sodium dihydrobis (2-methoxyethoxy)aluminate in benzene is added dropwise. After the addition is completed, the solution is allowed to warm to room temperature and stand for three days. The solution is then poured onto ice. The mixture is extracted thrice with chloroform. The combined chloroform extracts are dried over anhydrous magnesium sulfate, filtered from drying agent, then evaporated to dryness to obtain a crude orange oil product. The oil is chromatographed on a silica gel G column, eluting with benzene-triethylamine (200:1), to yield 2-(ochlorophenyl) 3,4-pentadien-2-ol.

Repeating the procedure of this example, but using in place of the 2-chloroacetophenone used in Step A, an approximately equivalent amount of:

a) 3-chloroacetophenone;

b) 2-chlorobenzaldehyde; or

c) 1 -(2-chlorophenyl)-1-propanone; there is accordingly obtained:

a) 2-(m-chlorophenyl)-3,4-pentadien-2-ol;

b) l-(o-chlorophenyl)-2,3-butadien-1-ol; or

c) 3-(o-chlorophenyl)-4,5-hexadien-3-ol.

What is claimed is:

l. The compound of the formula wherein R is a hydrogen atom, methyl or ethyl; and A is either ortho-chlorophenyl or meta-chlorophenyl.

2. A compound of claim 1 in which A is orthochlorophenyl.

3. The compound of claim 2 which is 2-(o-chlorophenyl )-3 ,4-pentadien-2-ol.

4. A compound of claim 1 in which R is methyl.

5. A compound of claim 1 in which A is a metachlorophenyl. 

1. THE COMPOUND OF THE FORMULA
 2. A compound of claim 1 in which A is ortho-chlorophenyl.
 3. The compound of claim 2 which is 2-(o-chlorophenyl)-3,4-pentadien-2-ol.
 4. A compound of claim 1 in which R is methyl.
 5. A compound of claim 1 in which A is a meta-chlorophenyl. 